The present invention relates to a process for the preparation of oxiranes from aldehydes or ketones, of aziridines from imines, or of cyclopropanes from alkenes.
It is known from WO95/11230 to prepare oxiranes, aziridines and cyclopropanes by reacting a diazo compound with an aldehyde, ketone, imine or alkene as appropriate in the presence of both a sulphide and either an organometallic or an inorganic reagent to form a sulphur ylide. As diazo compounds are difficult to handle due to their toxicity and explosive nature it would be advantageous to generate the diazo compounds in situ for this process thereby minimising the handling of these hazardous materials.
Thus, according to one aspect of the present invention there is provided a process for the preparation of an oxirane, aziridine or cyclopropane of formula (I), wherein X is oxygen, NR4 or CHR5; R1 is hydrogen, alkyl, aryl, heteroaromatic, heterocyclic or cycloalkyl; R2 is hydrogen, alkyl, aryl, heteroaromatic, CO2R8, CHR14NHR13, heterocyclic or cycloalkyl; or R1 and R2 join together to form a cycloalkyl ring; R3 and R10 are, independently, hydrogen, alkyl, aryl, heteroaromatic, CO2R8, R83Sn, CONR8R9, trialkylsilyl or triarylsilyl; R4 is an electron withdrawing group; R5 is alkyl, cycloalkyl, aryl, heteroaromatic, SO2R8, SO3R8, COR8, CO2R8, CONR8R9, PO(R8)2, PO(OR8)2 or CN; R8 and R9 are independently alkyl or aryl; and R13 and R14 are independently hydrogen, alkyl or aryl; the process comprising the steps of:
(a) degrading a compound of formula (II), (IIa), (IIb) or (IIc), wherein R3 and R10 are as defined above; Y is a cation; depending on the nature of Y, r is 1 or 2; and L is a suitable leaving group, to form a diazo compound of formula (III) wherein R3 and R10 are as defined above;
(b) reacting the compound of formula (III) with a suitable transition metal catalyst
(c) reacting the product of step (b) with a sulphide of formula SR6R7, wherein R6 and R7 are independently alkyl, aryl or heteroaromatic, or R6 and R7 join together to form an optionally substituted ring which optionally includes an additional heteroatom; and
(d) reacting the product of step (c) with a compound of formula (IV) wherein R1 and R2 are as defined above.
When the compound of formula (IV) is an alkene (that is, when X in the compound of formula (IV) is CHR5) it is an electron deficient alkene.
When the process of the present invention is used to prepare an oxirane (that is, a compound of formula (I) wherein X is O, it is necessary to balance the reactivity of the compound of formula (IV) against the reactivity of the product of step (c).
It is preferred that the compounds of formula (II) are degraded thermally (see, for example, Synth. Comm. 1978, 8(8) 569 or Bull. Soc. Chim. Belg. 1977, 86, 739); that the compounds of formula (IIa) are degraded by contacting the compounds with, for example, lead tetraacetate or manganese dioxide (see, for example, the procedure of Holton in J. Org. Chem. 1995, 60, 4725 and references cited therein); that the compounds of formula (IIb) are degraded thermally or by the action of light (hv) (see, for example, the procedure of Doyle in Tett. Lett. 1989, 30, 3049 and references cited therein); and that the compounds of formula (IIc) are degraded by thermal oxidation (see, for example, the procedure of Horner in Chem. Ber. 1961, 94, 279).
The process of the present invention can be carried out in the presence of a solvent. Suitable solvents include nitrites (such as acetonitrile), chlorinated solvents (such as CH2Cl2 or CHCl3), aromatic solvents (such as benzene, toluene and o-, m- or p-xylene), aliphatic alcohols (such as methanol, ethanol or tert-butanol), chain or cyclic ethers (such as diethyl ether, tert-butyl methyl ether, diisopropyl ether, glymes (for example monoglyme, diglyme or triglyme) or tetrahydrofuran), aliphatic or alicyclic hydrocarbons (such as n-hexane or cyclohexane), N,N-dimethylformamide, sulpholane, dimethylsulphoxide or N-methylpyrrolidone.
Alternatively, the process can be carried out in a mixture of miscible solvents (such as a mixture of water and acetonitrile), or different reagents may be added in different solvents.
Phase transfer reagents can be used during the process of the present invention (for example when the process of the invention is carried out in a solvent and the reaction mixture is not homogenous). Suitable phase transfer reagents include ammonium salts (such as benzyltriethylammonium chloride) or crown ethers.
It is preferred that the process of the present invention is carried out at a temperature in the range xe2x88x9230 to 100xc2x0 C., especially in the range 20 to 70xc2x0 C., such as at about 50xc2x0 C.
In preferred embodiments of the first aspect of the present invention, the compound of formula (II), (IIa), (IIb) or (IIc) is decomposed in the presence of the transition metal catalyst, the sulphide and the substrate compound of formula (IV).
According to a second aspect of the present invention, there is provided a process for the generation of diazo compounds, wherein a compound of formula II is thermally decomposed in the presence of an aprotic solvent and a phase transfer catalyst, but in the absence of free base.
In the process of the second aspect of the present invention, the aprotic solvent may comprise a nitrile (such as acetonitrile); a chlorinated solvent (such as CH2Cl2 or CHCl3); an aromatic solvent (such as benzene, toluene and o-, m- or p-xylene); a chain or cyclic ether (such as diethyl ether, tert-butyl methyl ether, diisopropyl ether, a glyme (for example monoglyme, diglyme or triglyme) or tetrahydrofuran); an aliphatic or alicyclic hydrocarbon (such as n-hexane or cyclohexane); N,N-dimethylformamide; sulpholane; dimethylsulphoxide or N-methylpyrrolidone. Acetonitrile is particularly preferred. Most preferably, the process according to the second aspect is carried out under anhydrous conditions, ie in the substantial absence of water. Preferred phase transfer catalysts include quaternary ammonium salts, particularly trialkylbenzyl and tetraalkyl ammonium halides, especially chlorides, and most preferably those wherein each alkyl is independently a C1-16 alkyl group. When the compound of formula II is a quaternary ammonium salt, the compound of formula II also serves as phase transfer catalyst. Most advantageously, the compound of formula II is substantially insoluble in the aprotic solvent, and is employed as a suspension. It is particularly preferred that the compound of formula II is a sodium salt. The thermal decomposition is often effected at a temperature of from 0 to 70xc2x0 C., preferably from about 15 to about 50xc2x0 C.
The compounds of formula (I) may have one, two or three chiral ring-carbon atoms and the process of the first aspect of the present invention is capable of forming all structural isomers of the compounds of formula (I). When one or more of R1, R2, R3, R4 or R5 is chiral it can affect the stereochemical nature of the compound of formula (I) produced by the process of the present invention.
The term alkyl whenever it is used refers to straight or branched alkyl chains preferably containing from 1 to 10, especially from 1 to 6, for example from 1 to 4, carbon atoms. Alkyl is, for example, methyl, ethyl, n-propyl, n-butyl or tert-butyl. All alkyl groups are optionally substituted. Preferred substituents are one or more of aryl (such as phenyl), aryloxy (such as phenoxy), heteroaromatic, heterocyclic (such as reduced forms of oxazole), cycloalkyl (such as cyclopropyl), C1-6 alkoxy (such as methoxy or ethoxy), C1-6 thioalkyl (such as methylthio), halogen (to form, for example, CCl3, CF3 or CH2CF3), C1-6 haloalkoxy (such as OCF3), cyano, hydroxy or CO2(C1-6)alkyl. In addition the alkyl groups of R5 may terminate with an aldehyde (C(H)xe2x95x90O) group or be interrupted with a carbonyl (Cxe2x95x90O) group.
Halogen is fluorine, chlorine, bromine or iodine.
Alkoxy and haloalkoxy groups are straight or branched chains, preferably containing from 1 to 4 carbon atoms.
Haloalkoxy and haloalkyl groups do not have a halogen that is susceptible to nucleophilic substitution. Thus, a carbon atom of a haloalkyl or haloalkoxy group must not carry a halogen atom and a hydrogen atom.
Cycloalkyl rings contain, preferably from 3 to 7, especially from 3 to 6 carbon atoms. Cycloalkyl rings, can be substituted by one or more alkyl groups, CO2R8 (wherein R8 is as defined above) or two ring carbons may be joined to each other by a carbon chain containing from 1 to 4 (preferably 1 or 2) carbon atoms to form a bicyclic structure.
Aryl includes naphthyl but is preferably phenyl.
Heteroaromatic includes 5- and 6-membered aromatic rings containing one, two, three or four heteroatoms selected from the list comprising oxygen, sulphur and nitrogen and can be fused to benzenoid ring systems. Examples of heteroaromatic rings are pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl (1,2,3-, 1,2,4- and 1,3,5-), furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl (1,2,3- and 1,2,4-), tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolinyl, isoindolinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazole, benzthiazole, oxadiazole and thiadiazole.
All aryl and heteroaromatic groups are optionally substituted. Preferred substituents include one or more of alkyl, haloalkyl, C1-6 alkoxy, halogen, C1-6 haloalkoxy, cycloalkyl, nitro, cyano or CO2(C1-6)alkyl.
Heterocyclic is used in relation to non-aromatic rings and includes include 5- and 6-membered rings containing one, two or three heteroatoms selected from the group comprising oxygen, sulphur and nitrogen. Examples are piperidine, pyrrolidine, azetidine, morpholine, tetrahydrofuran, tetrahydrothiophene, pyrroline, piperazine, isoxazoline, oxazoline and reduced forms of heteroaromatics not previously mentioned. Heterocyclic rings are optionally substituted and preferred substituents include one or more alkyl groups.
When the compound of formula (IV) is an aldheyde, R2 is preferably an optionally substituted alkyl group comprising from 1 to 10 carbon atoms; an optionally substituted phenyl group, particularly substituted at one or both of the positions ortho or para to the aldehyde moiety or an optionally substituted heteroaromatic group comprising a 5 or 6 membered ring, especially comprising 1,2 or 3 nitrogen heteroatoms.
When the compound of formula (IV) is a ketone, at least one of R1 and R2 often represents an optionally substituted alkyl group comprising from 1 to 10 carbon atoms, or forms a cycloalkyl group, and most often the carbon alpha to the keto group carries one, and preferably two hydrogen atoms. When one or both, preferably one, of R1 and R2 represents an aryl or heteroaromatic group, the ring positions adjacent to the keto group preferably carry hydrogen atoms. Aliphatic ketones, particularly those comprising up to 16 carbon atoms are most preferred.
When the compound of formula (IV) is an alkene, it is preferred that the alkene is conjugated with an electron withdrawing group, preferably a carbonyl, nitro, cyano phosphoryl or sulphonyl group, especially a group of formula SO2R8, SO3R8, COR8, CO2R8, CONR8R9, CN, P(O)(R8)2, especially P(O)(aryl)2 or PO(OR8)2; wherein R8 and R9 are as defined above. When R8 or R9 comprises an alkyl group, it is preferably a C1-6 alkyl group, which may be substituted. When R8 or R9 comprises an aryl group, it is preferably a phenyl group, which may be substituted.
When the compound of formula (IV) is an imine, it is preferred that one of R1 and R2 represents H, alkyl, phenyl or a heteroaromatic group, the other representing alkyl, aryl or a heteroaromatic group, wherein any alkyl group preferably comprises from 1 to 10 carbon atoms; and is optionally substituted; any phenyl group is optionally substituted, particularly at one or both of the positions ortho or para to the aldehyde moiety and any heteroaromatic group comprises a 5 or 6 membered ring, especially comprising 1,2 or 3 nitrogen heteroatoms, and is optionally substituted. R4 is an electron withdrawing group, such as a group of formula SO2R8, SO3R8, COR8, CO2R8, CONR8R9, CN, P(O)(R8)2, especially P(O)(aryl)2 or PO(OR8)2; wherein R8 and R9 are as defined above. When R8 or R9 comprises an alkyl group, it is preferably a C1-6 alkyl group, which may be substituted. When R8 or R9 comprises an aryl group, it is preferably a phenyl group, which may be substituted.
In the sulphides which are employed in the process of the first aspect of the present invention, it is preferred that at least one of R6 and R7 represents an alkyl group. In many embodiments, the sulphide is an aliphatic sulphide.
Examples of sulphides that can be employed include those compounds listed as structures (A) to (AB) below.
The ring formed when R6 and R7 join preferably contains from 1 to 12 (for example from 2 to 10, especially from 2 to 6 [see, for example, (B), (C) or (Cxe2x80x2)]) carbon atoms, optionally includes an additional heteroatom (preferably a nitrogen, oxygen or sulphur atom) [see, for example, (D) or (J)] and is optionally substituted. This ring may be fused to other rings (for example aryl [such as naphthyl, see, for example, (A)] or mono- or bi-cyclic carbon ring systems (such as cyclohexane [see, for example, (F), (G), (K) or (L)] or camphor [see, for example, (D) or (J)]) which are optionally substituted (for example substituted with alkyl, aryl or heteroaryl). When the cyclic sulphide is a 1,3-oxathiane, the 2-position is preferably unsubstituted or carries one substituent wherein the carbon alpha to the 2-position carries at least one, and preferably at least two hydrogen atoms, and particularly such substituents are primary or secondary alkyl groups. The ring may also incorporate carbon-carbon double bonds, and when such a double bond is present, there is preferably only one such bond in the ring also comprising the S atom. Cyclic sulphides may also be substituted by an alkenyl group, and, when present, such an alkenyl substituent particularly substitutes a ring fused to the ring comprising the sulphur atom.
A particular class of cyclic sulphides which can be employed in the process of the present invention has the general chemical formula (VI): 
wherein Z represents xe2x80x94CH2xe2x80x94, O, S, xe2x80x94CHalkyl-, C(alkyl)2xe2x80x94 or NR4, each of Rdxe2x88x92k independently represents H, alkyl or alkoxyalkyl or are linked to form a cyclic moiety, provided that at least 2 of Rd, Re, Rj and Rk represent H, and R4 is as hereinbefore defined. Advantageously, the nature of Rdxe2x88x92k is selected such that the sulphide is chiral.
In certain embodiments, two of Rdxe2x88x92k can be linked so as to form a bridging group, for example comprising 1 to 4 bridging atoms, or a fused cyclic group, for example forming a 5 or preferably 6, membered ring. In certain preferred embodiments, either Rd and Re or Rj and Rk are linked to form a cyclic group, preferably forming a 5-, or especially a 6-membered ring.
The compounds of formula (VI) where either Rd and Re or Rj and Rk are linked to form a cyclic group are novel and form an aspect of the present invention.
The compounds of formula (VI) wherein Z represents O, and the nature of the groups Rdxe2x88x92k are such that the compounds are chiral are novel and form an aspect of the present invention. In certain preferred compounds of formula (VI), one of Rd and Re and one of Rf and Rg, or one of Rh and Ri and one of Rj and Rk are linked to form a six membered ring. In other preferred compounds of formula (VI), both of Rf and Rg and one of Rd and Re are independently alkyl, especially C1-6 Alkyl or alkoxyalkyl, especially C1-4alkoxyC1-6alkyl, with the remainder of Rdxe2x88x92k representing hydrogen.
A further class of sulphides which may be employed in the process of the present invention have the chemical formula (VII) 
wherein Rm and Rn are each independently alkyl, especially C1-6 alkyl or alkoxyalkyl, especially C1-4alkoxyC1-6alkyl.
Alternatively, the sulphide of formula SR6R7 may be a bis-sulphide (such as (E)) or may be incorporated into the molecular structure of the organometallic compound (such as (H)).
The substituents referred to in structures (A)-(AB) are defined as follows: Rxe2x80x2, Rxe2x80x3 and Rxe2x80x2xe2x80x3 are, independently, hydrogen, alkyl, alkoxyalkyl, aryl or heteroaryl, and are particularly hydrogen, C1-6 alkyl or C1-4alkoxyC1-6alkyl; in (F), (G), (L) and (O) Rxe2x80x2 and Rxe2x80x3 may join to form a 3 to 8-membered carbocyclic ring optionally substituted with alkyl; in (D), Ra is hydrogen or primary or secondary unsubstituted, mono- or di-substituted alkyl, and Rb is hydrogen, alkyl, aryl or heteroaryl; Ra may also be CH2O(CH2)nO(CH2)mORb or (CH2)pCO(CH2)CORb; or alternatively Ra is linked to a polymer support; wherein n, m and p are integers (preferably 1-10); in (E), Rc is (Q) or (CH2)qSrxe2x80x2; R22 is hydrogen, alkyl or trialkylsilyl; and R23 is hydrogen or alkyl; wherein q is an integer of 2 or more (preferably 2-10). It is preferred that Rb is hydrogen.
The groups Ra and Rb in structure (D) are, for example:
In structures (P), (R), (S), (T), (U), (V), (W), (X), (Y), (Z), (AA) and (AB), the methyl and iso-propyl groups, particularly those methyl groups substituting the ring comprising the S atom, may be replaced by an alternative alkyl group, preferably a C1-6 alkyl group, most preferably a C1-4 alkyl group, or by an alkoxyalkyl group, preferably a C1-4alkoxyC1-6alkyl group, most preferably a C1-4 alkoxymethyl group.
Suitable transition metal catalysts are those which convert diazo compounds to carbenes, and include particularly rhodium, ruthenium, copper, nickel and palladium compounds, and especially complexes. When the transition metal catalyst comprises a rhodium compound, it is commonly a rhodium (0) or rhodium (II) compound, and preferably rhodium (II). When the transition metal catalyst comprises a ruthenium compound, it is commonly a ruthenium (0), (II) or (III) compound, and preferably a ruthenium (II) compound. When the transition metal catalyst comprises a copper compound, it is commonly a copper (0), (I) or (II) compound, including metallic Cu, and preferably a Cu(I) or (II) compound. When the transition metal catalyst comprises a nickel compound, it is commonly a nickel (0) or (II) compound, and preferably a nickel (II) compound. When the transition metal catalyst comprises a palladium compound, it is commonly a palladium (0) or palladium (II) compound, and preferably a palladium (II) compound.
Suitable transition metal catalysts preferably comprise rhodium or ruthenium. Suitable reagents include Rh2(OCOR.)4 or Ru2(OCOR.)4 [wherein R. is hydrogen, alkyl (preferably methyl), C1-4 perfluoroalkyl (such as trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl), aryl, (CHOH)alkyl or (CHOH)aryl], such as Rh2(OCOCH3)4 or Rh2(OCOCF3)4; or can be RuCl2(P(C6H5)3)2, RuCl(H2C2B9H10)(P(C6H5)3)2 or RH6(CO)16.
Alternatively, suitable transition metals comprise copper, nickel or palladium. Examples of suitable reagents include CuBr, CuCl, CuOSO2CF3, CuBr2, CuCl2, CuSO4, Cu(CH3CO2)2 a copper compound of formula (V) (wherein R20 and R21 are both methyl [that is, Cu(acetylacetonate)2], phenyl or tert-butyl, or R20 is phenyl and R21 is methyl), [Cu(CH3CN)4]BF4, NiBr2, NiCl2, NiSO4, Cu(CH3CO2)2, the nickel analogue of the compound of formula (V) (wherein R20 and R21 are both methyl [that is, Ni(acetylacetonate)2], phenyl or tert-butyl, or R20 is phenyl and R21 is methyl), Pd(OCOCH3)2, Pd(acetylacetonate)2, Pd(CH3CN)2Cl2 or Pd(C6H5CN)2Cl2.
Suitable cations (Y) for compounds of formula (II) are cations of alkali metals (especially sodium, potassium or lithium), cations of alkaline earth metals (such as magnesium or calcium) or quaternary ammonium salts [such as (C1-6 alkyl)4N+, wherein the alkyl group is unsubstituted, for example (CH3(CH2)3)4N+]. It is preferred that Y is the cation of sodium (that is, Na+).
Suitable leaving groups (L) for compounds of formula (II) include arylsulphonyl (that is arylSO2) compounds (wherein the aryl is mono-, di- or tri-substituted with unsubstituted C1-10 alkyl or is monosubstituted with nitro) or unsubstituted C1-10 alkylsulphonyl compounds. Examples of suitable leaving groups are p-tosyl, 2,4,6-tri-iso-propylphenylsulphonyl, 2-nitrophenylsulphonyl and mesyl.
The compounds of formula (II) can be prepared by adaptation of methods found in the literature. For example, the compounds wherein L is tosyl can be prepared from tosyl hydrazones by adapting the methods of Creary (Organic Synth. 1986, 64, 207), Bertz (J. Org. Chem. 1983, 48, 116) or Farnum (J. Org. Chem. 1963, 28, 870). Tosyl hydrazones can be prepared from tosyl hydrazides which can in turn be prepared by reacting tosyl hydrazine with an aldehyde of formula R3CHO.
In many embodiments, only one, or neither, of R3 and R10 represents hydrogen. Preferably one of R3 or R10 is an alkyl, aryl or amide group. When one of R3 or R10 represents a group of formula xe2x80x94CONR8R9, especially when X is O, it is preferred that the sulphide employed is not a 1,3-oxathiane.
It is preferred that the nucleophilicity of the sulphide of formula SR6R7 is such that the rate of reaction of the product of step (b) with the sulphide of formula SR6R7 is greater than the rate of reaction of the product of step (b) with the compound of formula (III).
It is possible to influence the stereochemistry of the compound of formula (I) produced by the process. This can be done by using a chiral sulphide of formula SR6R7 (such as structures (Cxe2x80x2), (D), (F), (G), (H), (J), (K) or (L), (M), (N), (O), (Oxe2x80x3), (P), and (R) to (AB)). The relative amounts of the stereochemical products will depend on the nature of the chiral sulphide used. Thus, in a further aspect the present invention provides a process as hereinbefore described wherein a chiral sulphide is used.
In another aspect the present invention provides a process as previously described wherein the organometallic reagent is present in a less than stoichiometric amount (such as from 0.5 to 0.001, for example from 0.015 to 0.005, equivalents).
In a further aspect the present invention provides a process as previously described wherein a less than a stoichiometric amount of sulphide is used in relation to the amount of compound of formula (IV). For example it is preferred that the amount of sulphide used is in the range 1.00-0.01 equivalents (such as in the range 0.75-0.02 (for example 0.5-0.05 (particularly about 0.2)) equivalents).
In a further aspect the present invention provides a process as hereinbefore described wherein a chiral sulphide is used in an amount in the range of 0.5-0.1 equivalents relative to the amount of compound of formula (IV) used.
In a still further aspect the present invention provides a process as hereinbefore described wherein the compound of formula (IV) is an aldehyde, ketone, imine or alkene.
In another aspect the present invention provides a process as defined above wherein X is oxygen.
In a further aspect the present invention provides a process for preparing a compound of formula (I) wherein X is oxygen and R1 is hydrogen, and the process is conducted under the following conditions:
In a still further aspect the present invention provides a process for preparing a compound of formula (I) wherein X is oxygen, wherein: a compound of formula (II) (wherein Y is Na+) is used in step (a) and this compound is degraded in situ at low temperature for extended reaction times (typically 30xc2x0 C. for 32 hours) and acetonitrile is used as solvent. In another aspect the sulphide of formula R6R7 is used in 100 mol %.
In a further aspect the present invention provides a process as hereinbefore described wherein a compound of formula (II) is used in step (a). In another aspect the present invention provides a process as hereinbefore described wherein and using a compound of formula (II) in step (a) wherein the compound of formula (II) is prepared from the corresponding hydrazone (that having been prepared by contacting the corresponding aldehyde or ketone with a suitable hydrazide).
In a still further aspect the present invention provides a process for the preparation of a compound of formula (I), the process comprising:
1. adding a compound of formula (II) to a mixture of:
a compound of formula (IV),
a sulphide of formula SR6R7 and
either a rhodium compound of formula Rh2(OCOR.)4 (wherein R. is preferably methyl) or a copper (II) acetoacetonate,
a solvent (preferably acetonitrile or a mixture of acetonitrile and water) and, optionally,
a phase transfer catalyst (preferably benzyltriethylammonium chloride);
2. heating the resulting mixture to a temperature in the range 20-60xc2x0 C. for a time period (preferably 1-48 hours); and
3. extracting the compound of formula (I) from the mixture so formed.
The following Examples illustrate the invention. The following abbreviations are used throughout the Examples:
All solvents used in reactions were distilled prior to use. Tetrahydrofuran (THF) and diethyl ether were freshly distilled from sodium under an atmosphere of dry nitrogen using benzophenone as an indicator. Acetonitrile and dichloromethane (DCM) were freshly distilled from calcium hydride. Reagents were either used as received from commercial sources or purified by recognised methods. Petroleum ether (petrol) refers to that fraction which boils in the range 40-65xc2x0 C. Liquid aldehydes were distilled prior to use, either neat or from calcium sulphate. Copper (II) acetylacetonate was sublimed prior to use.
All reactions, unless otherwise stated, were carried out in oven dried glassware under an atmosphere of dry nitrogen or argon.
Flash chromatography was performed using Kieselgel 60 F254 and on C560, 40-63 micron silica gel. All reactions were monitored by thin layer chromatography (TLC) carried out on aluminium sheets precoated with 60F254 silica gel, unless otherwise stated, and were visualised by UV light at 254 nm, then potassium permanganate solution, phosphomolybdic acid (PMA) solution or anisaldehyde solution (epoxides appeared to stain very intensely with PMA solution).
1H-NMR were recorded on a Bruker ACF-250 spectrometer operating at 250.13 MHz or a Bruker WH400 instrument operating at 399.7 MHz. The observed spectra were for solutions in deuterochloroform unless otherwise stated. The chemical shifts (d) were recorded in parts per million (ppm) relative to tetramethylsilane as an internal standard; all coupling constants, J, are reported in Hz.
13C-NMR spectra were recorded on a Bruker ACF-250 spectrometer operating at 62.9 MHz. The spectra were recorded for solutions in deuterochloroform unless otherwise stated. The chemical shift (d) were recorded relative to deuteriochloroform (or relative solvent peak) as internal standard in a broad band decoupled mode; the multiplicities were obtained by using 135xc2x0 and 90xc2x0 xe2x80x9cDistortionless Enhancement by Polarisation Transferxe2x80x9d (DEPT) or Off Resonance Decoupling experiments to aid in assignments (q, methyl; t, methylene; d, methine; s, quaternary).
Infra red spectra were recorded on a Perkin-Elmer 157G FT-IR, either as liquid films between sodium chloride plates or as KBr discs.
Mass spectra were recorded on a Kratos MS 25 or MS 80 instrument with a DS 55 data system using either an ionising potential of 70 eV (EI), or by chemical ionisation (iso-butane) (CI) or fast atom bombardment (FAB) in 3NBA matrix.
Melting points (m.p.) were recorded on a Kofler Hot Stage Micro Melting Point Apparatus and are uncorrected.
Optical rotations were recorded on a Perkin-Elmer 141 Polarimeter at ambient temperature. [a] values are reported as 10xe2x88x921 deg cm2 gxe2x88x921. Microanalysis was carried out on a Perkin-Elmer 2400 Elemental Analyser.
High pressure liquid chromatography (HPLC) analysis, used to determine enantiomeric excesses, was carried out using a Gilson 303 HPLC pump, Waters 994 Tuneable Absorbance Detector or a Waters 2200 Data Module (analysis conditions are given below).
Diastereomeric ratios were determined by NMR analysis.